US2012035268A1PendingUtilityA1
Sphingo-guanidines and their use as inhibitors of sphingosine kinase
Individually held — no corporate assignee on recordPriority: Dec 30, 2008Filed: Dec 28, 2009Published: Feb 9, 2012
Est. expiryDec 30, 2028(~2.4 yrs left)· nominal 20-yr term from priority
A61P 9/10A61P 35/04A61P 37/00A61P 35/00A61P 9/00A61P 29/00A61P 17/02A61P 11/06C07C 279/08A61P 17/00A61K 31/155
48
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Claims
Abstract
The presently disclosed subject matter provides compounds of the formula: (1) and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are as defined herein. Also disclosed are methods for making the compounds of the formula as set forth hereinabove, their use in inhibiting sphingosine kinase, and their use in the treatment and/or prevention of diseases and/or conditions associated with undesirable ceramidase or sphingosine kinase activity, including, but not limit cancer, cancer metastasis, atherosclerosis, stenosis, inflammation, immunological disorders, asthma, atopic dermatitis, wound healing, and other proliferative diseases.
Claims
exact text as granted — not AI-modified1 . A compound of Formula (I):
wherein:
R 1 is selected from the group consisting of H, alkyl, OH, (═O), (═N—OH), and SH;
R 2 is selected from the group consisting of H, alkyl, OH, SH, (═O), and (═N—OH);
R 3 is selected from the group consisting of H, alkyl, substituted alkyl, unsaturated alkyl, aryl, substituted aryl, aralkyl, OH, alkoxyl, aryloxyl, aralkoxyl, amino, aminoalkyl, an aminoacid moiety, and a peptidyl moiety;
R 4 and R 5 are independently selected from the group consisting of H, C(═NH)—NH 2 , acyl, alkyl, substituted alkyl, aralkyl, aryl, and substituted aryl;
R 6 is selected from the group consisting of H, CN, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, and acyl;
R 7 is selected from the group consisting of H, alkyl, substituted alkyl, aralkyl, aryl, and substituted aryl; and
R 8 is present or absent, and when present is selected from the group consisting of H, alkyl, substituted alkyl, aralkyl, aryl, and substituted aryl;
or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 , wherein R 1 is selected from OH and H.
3 . The compound of claim 1 , wherein R 2 is selected from OH, (═O), and H.
4 . The compound of claim 1 , wherein R 1 and R 2 are each OH.
5 . The compound of claim 1 , wherein R 3 is selected from C 15 fully saturated alkyl, C 15 hydroxy-substituted alkyl, C 15 alkenyl, C 15 alkynyl, aralkyl, phenyl, and H.
6 . The compound of claim 1 , wherein R 4 is H.
7 . The compound of claim 1 , wherein R 5 is H.
8 . A pharmaceutically acceptable salt of a compound of claim 1 , wherein the pharmaceutically acceptable salt of the compound of claim 1 has a structure of Formula (Ia):
wherein:
R 1 is selected from the group consisting of H, alkyl, OH, (═O), (═N—OH), and SH;
R 2 is selected from the group consisting of H, alkyl, OH, SH, (═O), and (═N—OH);
R 3 is selected from the group consisting of H, alkyl, substituted alkyl, unsaturated alkyl, aryl, substituted aryl, aralkyl, OH, alkoxyl, aryloxyl, aralkoxyl, amino, aminoalkyl, an aminoacid moiety, and a peptidyl moiety;
R 4 and R 5 are independently selected from the group consisting of H, C(═NH)—NH 2 , acyl, alkyl, substituted alkyl, aralkyl, aryl, and substituted aryl;
R 6 is selected from the group consisting of H, CN, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, and acyl;
R 7 is selected from the group consisting of H, alkyl, substituted alkyl, aralkyl, aryl, and substituted aryl;
R 3 is present or absent, and when present is selected from the group consisting of H, alkyl, substituted alkyl, aralkyl, aryl, and substituted aryl; and
A is selected from the group consisting of bromide, chloride, sulfate, acetate, dichloroacetate, benzoate, and tartrate.
9 . The pharmaceutically acceptable salt of claim 8 , wherein A is chloride.
10 . The compound of claim 1 , wherein the compound is selected from the group consisting of D-erythro-2-guanidino-sphingosine hydrochloride and L-erythro-2-guanidino-sphinogosine hydrochloride.
11 . A method of inhibiting sphingosine kinase, the method comprising contacting a sample comprising sphingosine kinase with an effective amount of a compound of Formula (I):
wherein:
R 1 is selected from the group consisting of H, alkyl, OH, (═O), (═N—OH), and SH;
R 2 is selected from the group consisting of H, alkyl, OH, SH, (═O), and (═N—OH);
R 3 is selected from the group consisting of H, alkyl, substituted alkyl, unsaturated alkyl, aryl, substituted aryl, aralkyl, OH, alkoxyl, aryloxyl, aralkoxyl, amino, aminoalkyl, an aminoacid moiety, and a peptidyl moiety;
R 4 and R 5 are independently selected from the group consisting of H, C(═NH)—NH 2 , acyl, alkyl, substituted alkyl, aralkyl, aryl, and substituted aryl;
R 6 is selected from the group consisting of H, CN, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, and acyl;
R 7 is selected from the group consisting of H, alkyl, substituted alkyl, aralkyl, aryl, and substituted aryl; and
R 5 is present or absent, and when present is selected from the group consisting of H, alkyl, substituted alkyl, aralkyl, aryl and substituted aryl;
or a pharmaceutically acceptable salt thereof.
12 . The method of claim 11 , wherein the compound selectively inhibits sphingosine kinase 1.
13 . The method of claim 11 , wherein the compound is essentially completely water soluble.
14 . The method of claim 11 , wherein the sample is an in vitro sample.
15 . The method of claim 11 , wherein the compound inhibits sphingosine kinase with a 50% inhibitory concentration (IC 50 ) of less than about 1.0 μM.
16 . The method of claim 15 , wherein the compound inhibits sphingosine kinase with an IC 50 of less than about 0.4 μM.
17 . The method of claim 11 , wherein R 1 is selected from OH and H.
18 . The method of claim 11 , wherein R 2 is selected from OH, (═O), and H.
19 . The method of claim 11 , wherein R 1 and R 2 are each OH.
20 . The method of claim 11 , wherein R 3 is selected from C 15 fully saturated alkyl, C 15 hydroxy-substituted alkyl, C 15 alkenyl, C 15 alkynyl, aralkyl, phenyl, and H.
21 . The method of claim 11 , wherein R 4 is H.
22 . The method of claim 11 , wherein R 5 is H.
23 . The method of claim 11 , wherein the compound is contacted to the sample in the form of a pharmaceutically acceptable salt.
24 . The method of claim 23 , wherein the pharmaceutically acceptable salt is a hydrochloride salt.
25 . The method of claim 11 , wherein the compound is selected from the group consisting of D-erythro-2-guanidino-sphingosine hydrochloride and L-erythro-2-guanidino-sphinogosine hydrochloride.
26 . A method of treating or preventing a disease or disorder associated with undesirable ceramidase or sphingosine kinase activity in a subject, the method comprising administering to the subject an effective amount of a compound of Formula (I):
wherein:
R 1 is selected from the group consisting of H, alkyl, OH, (═O), (═N—OH), and SH;
R 2 is selected from the group consisting of H, alkyl, OH, SH, (═O), and (═N—OH);
R 3 is selected from the group consisting of H, alkyl, substituted alkyl, unsaturated alkyl, aryl, substituted aryl, aralkyl, OH, alkoxyl, aryloxyl, aralkoxyl, amino, aminoalkyl, an aminoacid moiety, and a peptidyl moiety;
R 4 and R 5 are independently selected from the group consisting of H, C(═NH)—NH 2 , acyl, alkyl, substituted alkyl, aralkyl, aryl, and substituted aryl;
R 6 is selected from the group consisting of H, CN, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, and acyl;
R 7 is selected from the group consisting of H, alkyl, substituted alkyl, aralkyl, aryl, and substituted aryl; and
R 8 is present or absent, and when present is selected from the group consisting of H, alkyl, substituted alkyl, aralkyl, aryl and substituted aryl;
or a pharmaceutically acceptable salt thereof, wherein said compound inhibits sphingosine kinase.
27 . The method of claim 26 , wherein the compound selective inhibits sphingosine kinase 1.
28 . The method of claim 26 , wherein the compound is essentially completely water soluble.
29 . The method of claim 26 , wherein the disease or disorder is selected from the group consisting of cancer, cancer metastasis, atherosclerosis, stenosis, inflammation, an immunological disorder, asthma, atopic dermatitis, wound healing and other proliferative diseases.
30 . The method of claim 26 , wherein the subject is a mammalian subject.
31 . The method of claim 26 , wherein the compound of Formula (I) is administered to the subject in a pharmaceutical formulation comprising the compound of Formula (I) and a pharmaceutically acceptable carrier.
32 . A method of treating cancer, the method comprising administering to a subject in need of treatment thereof an effective amount of a compound of Formula (I):
wherein:
R 1 is selected from the group consisting of H, alkyl, OH, (═O), (═N—OH), and SH,
R 2 is selected from the group consisting of H, alkyl, OH, SH, (═O), and (═N—OH);
R 3 is selected from the group consisting of H, alkyl, substituted alkyl, unsaturated alkyl, aryl, substituted aryl, aralkyl, OH, alkoxyl, aryloxyl, aralkoxyl, amino, aminoalkyl, an aminoacid moiety, and a peptidyl moiety;
R 4 and R 5 are independently selected from the group consisting of H, C(═NH)—NH 2 , acyl, alkyl, substituted alkyl, aralkyl, aryl, and substituted aryl;
R 6 is selected from the group consisting of H, CN, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, and acyl;
R 7 is selected from the group consisting of H, alkyl, substituted alkyl, aralkyl, aryl, and substituted aryl; and
R 8 is present or absent, and when present is selected from the group consisting of H, alkyl, substituted alkyl, aralkyl, aryl, and substituted aryl;
or a pharmaceutically acceptable salt thereof.
33 . The method of claim 32 , wherein the cancer is selected from the group consisting of breast cancer, prostate cancer, and non small cell lung cancer.
34 . The method of claim 32 , wherein the subject is a mammalian subject.
35 . The method of claim 32 , wherein the compound of Formula (I) is administered in a pharmaceutical formulation comprising the compound of Formula (I) and a pharmaceutically acceptable carrier.
36 . The method of claim 32 , wherein R 1 is selected from OH and H.
37 . The method of claim 32 , wherein R 2 is selected from OH, (═O), and H.
38 . The method of claim 32 , wherein R 1 and R 2 are each OH.
39 . The method of claim 32 , wherein R 3 is selected from C 15 fully saturated alkyl, C 15 hydroxy-substituted alkyl, C 15 alkenyl, C 15 alkynyl, aralkyl, phenyl, and H.
40 . The method of claim 32 , wherein R 4 is H.
41 . The method of claim 32 , wherein R 5 is H.
42 . The method of claim 32 , wherein the compound is administered in the form of a pharmaceutically acceptable salt.
43 . The method of claim 42 , wherein the pharmaceutically acceptable salt is a hydrochloride salt.
44 . The method of claim 32 , wherein the compound is selected from the group consisting of D-erythro-2-guanidino-sphingosine hydrochloride and L-erythro-2-guanidino-sphinogosine hydrochloride.
45 . The method of claim 32 , wherein treating cancer comprises preventing the metastasis of a cancer.Join the waitlist — get patent alerts
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